Personalised Regional Modelling Predicts Tau Progression in the Human Brain

Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer’s disease, and its accumulation exhibits a rich spatio-temporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatio-temporal process is orchestrated – namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production or both. To address this, we develop a mechanistic model from tau PET data to describe tau dynamics along the Alzheimer’s disease timeline. Our analysis reveals longitudinal changes in production and transport dynamics on two independent cohorts, with subjects in early stage of the disease exhibiting transport-dominated spread, consistent with an initial spread of pathologic tau seeds, and subjects in late stage disease (Braak stage 3/4 onwards) characterised primarily by local production of tau. Furthermore, we demonstrate that the model can accurately predict subject-specific longitudinal tau accumulation at a regional level, potentially providing a new clinical tool to monitor and classify patient disease progression. Teaser A mechanistic model reveals tau protein dynamics in Alzheimer’s, showing stage-specific shifts in transport and local production. ### Competing Interest Statement The authors have declared no competing interest.